Quaternary ammonium compounds



United States PatentC QUATERNARY AMMONIUM COMPOUNDS Martin Schenck, Berlin-Frohnau, Germany, assignor t Sehering A. G., Berlin, Germany, a corporation of Germany No Drawing. Application July 22, 1953, Serial No. 369,729

8 Claims. (Cl. 260-309.2)

The present invention relates to benzimidazol compounds, and more particularly to benzimidazol compounds which have in Z-position an aliphatic side chain wherein one hydrogen atom is substituted by a quaternizated tertiary amino group, and to a method of making same.

It is one object of this invention to provide new benzimidazol compounds which are useful as antihistaminic drugs.

Another object of this invention is to provide simple and elfective processes of producing such new benzimidazol compounds which have a high antihistam-inic activity.

Other objects and advantageous features of this invention will become apparent as the description proceeds.

The new benzimidazol derivatives according to the present invention are quaternary ammonium compounds of benzimidazol compounds of the following formula In this formula X represents a phenyl residue or a heterocyclic residue of the thiophene or furan type linked to the CI-Iz-group by a carbon atom whereby the phenyl residue or the heterocyclic residue may be substituted by halogen, a lower alkyl residue, or a lower allroxy group, while Y is a dimethylamino group and 11 indicates the integers 1 or 2.

The new quaternary ammonium compounds maybe produced by converting said tertiary benzimidazol bases of the above given Formula I, by means ofmethylati-ng quaternizing agents, into their quaternary ammonium compounds whereby the nitrogen atom is transformed from its three-valent state into the five-valent state. This conversion of said bases considerably increases their antihistaminic activity. Thus, for instance, the reaction product obtained according to the present invention by quateruization of 1-(p-chlorobenzyl)-2-dimethyl amino methyl benzimidazol by means of methyl chloride or methyl bromide is a very effective antihistaminic agent.

The new quaternary ammonium compounds maybe produced in various ways. One may, for instance, cause imidazol derivatives of the above given Formula I, Which are obtainable according to methods described in copending patent application Serial No. 211,198 of Martin Schenck and Wilhelm Heinz, filed February 15, 1951,

now Patent No. 2,689,853, to react with conventional quaternization agents, such as methyl halogenides, dimethyl sulfate, aryl sulfonic acid methyl esters and the like.

Quaternization according to the present invention shall also comprise the reaction of chlorohydrates of the above mentioned imidazol derivatives with methanol.

Another method of preparing said quaternary amice 2 monium compounds comprises the reaction of halogen containing intermediate compounds of the following Formula II directly with trimethylamine according to the following equation instead of with secondary amines.

This last mentioned process may be modified inasmuch as the substituent cHz X may be subsequently introduced into the molecule 'Whereby the corresponding intermediate product, after quaternization, is reacted, for

v instance, with benzyl halogenide or any other halogenide capable of introducing a CH2-X group into the molecule.

The methods of preparing the new quaternary ammonium compounds of 'benz-imidazol derivatives are, of course, given herein only as examples of ways and means of producing said compounds without limiting this invention to such methods. In principle, the new compounds may be produced either from corresponding imidazol compounds by reaction with quaternizing means or by first producing quaternary ammonium compounds of suitable intermediate products and then converting said quaternary ammonium intermediate compounds into the desired new compounds.

Quaternization is eflfected at room temperature or at elevated temperature, preferably While shaking in a sealed heavy-Walled glass tube or in an autoclave. As stated above, alkyl halogenides, such as methyl chloride or methyl bromide, alkyl sulfates, such as dimethyl sulfate, p-toluene sulfonic acid methyl ester and the like may be used as'such quaternization agents.

The reaction mixture may be diluted by the addition of suitable diluting agents, such as ether, acetone, benzene, alcohol, nitromethane and others.

The quaternary ammonium compounds according to the present invention are White, crystalline substances which are more or less soluble in water or alcohol. Some of them crystallize together with water of crystallization.

Of special importance are those benzimidazol compounds according to the present invention which have in l-position a benzyl residue substituted in p-position. The anion of the quaternary ammonium compound, however, is of minor importance.

The following starting materials are, for instance, especially suitable for the production of methylated quaternary ammonium compounds according to this invention:

l-benzyl-Z-dimethylamino methyl benzimidazol,

l-benzyl-2-(l'-dimethylamino ethyl) benzimidazol,

1-benZyl-2-(2'-dimethyla1nino ethyl) benzimidazol, and

the corresponding 1-( p-ehlorobenzyl) benzyl),

l-(p-methyl benzyl), l-( p-methoxy benzyl), l-(thienyl- Z'methyl),

l-(chloro thienyl-2'-methyl) derivatives of said benziidazol compounds.

The following examples serve to illustrate this invention without, however, limiting the same thereto.

EXAMPLE 1 1-benzyl-Z-dimethylamino methyl benzimidazol chloromethylate 26 g. of l-benzyl-2-chloro methyl benzimidazol obtained according to Example 1 of copending application Serial No. 211,198, filed February 15, 1951, Patent No. 2,689,853, are shaken at room temperature in a sealed heavy-walled glass tube for 3 hours with 200 cc. of ether and 15 cc. of trimethylamine. The mixture is allowed to stand overnight and the precipitated needles are filtered off by suction. They are washed with ether. Yield: 27 g. On dissolving said product in a small amount of alcohol and precipitating with ether, a product is obtained which melts at 209 C. (with decomposition). The new compound is readily soluble in water and alcohol and contains /2 mol of water of crystallization.

EXAMPLE 2 I-(p-chloro benzyl)-2-dimethylamino methyl benzimidazol chloromethylate To 9.0 g. of l-(p-chloro benzyl)-2-dimethylamino methyl benzirnidazol obtained according to Example 1 of copending application Serial No. 211,198, filed February 15, 1951, by using p-chloro benzylamine in the place of benzylarnine as starting material, there are added 100 cc. of ether and an excess of methylchloride. The mixture is shaken in a sealed heavy-walled tube overnight, and is worked up after three days. White needles melting at 215-217 C. (with decomposition) are obtained containing 2 mols of water of crystallization. The compound is readily soluble in water and alcohol.

The same compound is obtained by reacting l-(pchloro benzyl)-2-ch1oro methyl benzimidazol with trimethylamine in an analogous manner as described in Example 1.

In the place of l-benzyl-2-chloro methyl benzirnidazol, used as starting material in Example l, there may be used equimolecular amounts of:

l-(p-bromo benzyl)-2-bromo methyl benzimidazol l-(p-fluoro benzyl) -2-chloro methyl benzimidazol l-(p-methyl benzyl)-2-chloro methyl benzimidazol l-(p-ethyl'benzyl)-2-chloro methyl benzimidazol l-(p-methoxy benZyl)-2-chloro methyl benzimidazol l-(p-ethoxy benzyl)-2-chloro methyl benzimidazol l-(thienyl-2-methyl) 2-chloro methyl benzimidazol 1-(5-chloro tl1ienyl-2-methyl)-2-chloro methyl benzimidazol l-(5-methyl thienyl-2-methyl)-2-chloro methyl benzimidazol 1-(5'-methoxy thienyl-Z-methyl)-2-chloro methyl bcnzimidazol I-(furyI-T-methyl)-2-chl.o1'o methyl benzimidazol l-(5-chloro furyl2'-methyl)-2-chloro methyl benzimidazol l-(5-methyl furyl-2-methyl)-2-chloro methyl benzimidazol l-(5-methoxy furyl-2-methyl)-2-chloro methyl benzimidazol l-benzyl-2-(2chloro ethyl) benzimidazol l-benzyl-2-(l'-chloro ethyl) benzimidazol l-(p-chloro benzyl)-2-(2'-chloro ethyl) benzirnidazol l-(p-chloro benzyl)-2-(1'-chloro ethyl) benzimidazol l.-(p-bromo benzyl)-2-(1-bromo ethyl) benzirnidazol l-(p-methyl benzyl)-2-(1-chloro ethyl) benzimidazol l-(p-ethyl benzyl)-2-(l'-chloro ethyl) benzimidazol l-(p-methoxy benzyl)-2-(l'-chloro ethyl) benzimidazol l-(thienyl-2'-methyl)-2-( 1'-chloro ethyl) benzimidazol midazol l-(furyl-2-methyl)-2-(l-chloro ethyl) benzimidazo 1-(5'-chloro furyl-2'-methyl)-2-(l'-chloro ethyl) benzimidazol Likewise, in the place of 1-(p-chloro benzyU-Z-dimethylamino methyl benzimidazol, used as starting material in Example 2, there may be employed equimolecular amounts of:

l-benzyl-Z-dimethylamino methyl benzimidazole l-(p-bromo benzyl)-2-dirnethylamino methyl benzimidazol l-(p-fluorbenzyl)-2-dimethylamino methyl benzimidazol l-(p-methyl benzyl)-2-climethylamino methyl benzimidazol 1-(pethyl benzyl)-2-dimethylamino methyl benzimiclazol l-(p-methoxy benzyl)-2-dimethylarnino methyl benzimidazol l-(p-ethoxy benzyl)-2-dimethylamino methyl benzimidazol l-(thienyl-2-methyl)-2-dimethylamino methyl benzimidazol l-(5-chloro thienyl-2-methyl)-2-dimethylamino methyl benzimidazol l-(5-methyl thienyl-2-methyl)-2-dimethylamino methyl benzimidazol 1-(5 '-methoxy thienyl-2-methyl)-2-dimethylamino methyl benzimidazol l-(furyl-2-methyl)-2-ciimethylamino methyl benzirnidazol l-(5-chloro furyl-2'-methyl)-2dimethylamino methyl benzimidazol 1-(5'-methyl furyl-2-methyl)-2-dimethylamino methyl benzimidazol 1-(5'-methoxy furyl-2-methyl)-2dimethylamino methyl benzimidazol 1-benzyl-2-(2-dimethylarnino ethyl) benzimidazol l-benzyl-2-(1'-dimethylamino ethyl) benzimidazol l-(p-chloro benzyl-2-(2'-dimethylamino ethyl) benzimidazol l-(p-chloro benzyl)-2-(l'-dimethylamino ethyl) benzimidazol l-(p-bromo benzyl)-2-(l-dimethylaniino ethyl) benzimidazol l-(p-methyl benzyl)-2-(1-dimethylamino ethyl) benzimidazol l-(p-ethyl benZyl)-2-(l-dimethylamino ethyl) benzimidazol 1-'(p-methoxy benzyl)-2-(l-dimethylamino ethyl) benzimidazoll-(thienyl-2-methyl) -2-( 1-dimethylamino ethyl) benzimidazol l-(S' chloro thienyl 2' methyl) 2 (1 dimethylamino ethyl) benzimidazol l-(furyl-2-methyl)-2-(1-dimethylamino ethyl) benzimicL azol l-(5'-chloro furyl-2-methyl)-2-(l-dimethylamino cthyl) benzimidazol 1-(furyl-4'-methyl)2-dimethylamino methyl bcnzimidazol 1-(5-chloro furyl-2-methyl) -2-(2'-dimethylamino ethyl) benzimidazol l-(5' bromo thienyl 2' methyl) 2 (1 dimethylamino ethyl) benzimidazol Of course, other changes and variations in the reaction conditions, reaction temperature and duration, in the methods of working up and purifying the resulting quaternary ammonium compounds and the like may be made by those skilled in the art in accordance with the principles set forth herein and in the claims annexed hereto.

The new antihistaminic drugs are preferably administered orally either in the form of tablets, pills, lozenges, and other solid form, or in the form of their solutions in water, isotonic sodium chloride solution, sirup, dilute alcohol, or the like. They may also be topically applied, for instance, in the form of ointments, creams, and the like. They may be administered in the form of aerosols. In-

, jectable solutions thereof may also be prepared. The

average adult dose is between about 5 mg. and 10 mg. three to four times daily, which dose may be reduced to between 5 mg. and 10 mg. twice daily, if adequate respouse is obtained.

Thus when using the new quaternary ammonium compounds in the place of old antihistaminic drugs and also of the starting bases as described in application Serial No. 211,198 (Patent No. 2,689,853) the advantage will be frequently a considerable reduction of the dose needed.

When introducing the CHz-X group into the intermediate quaternary ammonium compound, there may be used in the place of benzyl halogenide, any other suitable halogenide, such as p-halogeno benzyl halogenide, palkoxy benzyl halogenide, p-alkyl benzyl halogenide and the halogenides of thienyl methyl, halogeno thienyl methyl, alkoxy thienyl methyl, furyl methyl, halogeno furyl methyl, alkoxy furyl methyl and alkyl furyl methyl.

To obtain new quaternary benzimidazol compounds wherein the non-toxic anion is another than mentioned there is also possible to convert one into another, for instance the chloromethylates into the corresponding phosphoric acid compounds, by using methods known in the art, e. g. according to the process described in the German patent application M 11,099, 12q, 1/01, published November 13, 1952.

I claim: 1. A benzimidazole compound of the following formula CHFX wherein X is a member selected from the group consisting of phenyl, halogenated phenyl, lower alkyl substituted wherein Hal is halogen and Z is a halogen anion having a molecular weight of at least that of chlorine.

3. A benzimidazol compound of the following formula 10 cHa wherein A is a lower alkyl radical and Z is a halogen anion having a molecular weight of at least that of chlorine.

15 4. A benzimidazol compound of the following formula References Cited in the file of this patent UNITED STATES PATENTS Schenck et al Sept. 23, 1954 OTHER REFERENCES Idson: Chem. Reviews, vol. 47, pp. 493, 499 (1950). 

1. A BENZIMIDAZOLE COMPOUND OF THE FOLLOWING FORMULA 